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Appendicitis is one of the most common causes of acute abdominal pain in adults and children, with a lifetime risk of 8.6% in males and 6.7% in females. It is the most common nonobstetric surgical emergency during pregnancy. Findings from the history, physical examination, and laboratory studies aid in the diagnosis of acute appendicitis. Right lower quadrant pain, abdominal rigidity, and periumbilical pain radiating to the right lower quadrant are the best signs for ruling in acute appendicitis in adults. Absent or decreased bowel sounds, a positive psoas sign, a positive obturator sign, and a positive Rovsing sign are most reliable for ruling in acute appendicitis in children. The Alvarado score, Pediatric Appendicitis Score, and Appendicitis Inflammatory Response score incorporate common clinical and laboratory findings to stratify patients as low, moderate, or high risk and can help in making a timely diagnosis. Recommended first-line imaging consists of point-of-care or formal ultrasonography. Appendectomy via open laparotomy or laparoscopy is the standard treatment for acute appendicitis. However, intravenous antibiotics may be considered first-line therapy in selected patients. Pain control with opioids, nonsteroidal anti-inflammatory drugs, and acetaminophen should be a priority and does not result in delayed or unnecessary intervention. Perforation can lead to sepsis and occurs in 17% to 32% of patients with acute appendicitis. Prolonged duration of symptoms before surgical intervention raises the risk. In moderate- to high-risk patients, surgical consultation should be accomplished quickly to reduce morbidity and mortality resulting from perforation.

Key Points Haplotypes link together (that is, 'phase') groups of genetic variants that co-occur on single chromosomes. Although haplotypes have an important role in clinical genetics and association studies, they are not typically obtained by contemporary genotyping or sequencing technologies and must be determined separately. Inferential methods for haplotype determination perform fairly poorly for the rare and private variants implicated in many genetic diseases. To phase this class of variants accurately and comprehensively, direct experimental methods are needed. Dense haplotyping methods comprehensively phase variants into haplotype blocks at the scale of a single gene or a small number of genes and corresponding regulatory regions. Contiguity is defined within each block but not between adjacent or distant haplotype blocks. Sparse haplotyping methods phase a more modest number of distant variants distributed along an entire chromosome or a chromosome arm. Resulting haplotypes are not comprehensive but have long-range contiguity that is currently unattainable using dense methods. Reference panels of previously ascertained haplotypes can be used to correct errors in, or increase the density or contiguity of, directly obtained haplotypes. Such hybrid approaches yield improved haplotypes at low costs. Although contiguity metrics are typically used to compare haplotype assemblies, comprehensive comparisons should also include measures of the accuracy, density and allele frequency spectrum of the phased variants. High-throughput DNA sequencing technologies are providing an ever-expanding wealth of genome sequence data, including detailed information on human genetic variation. However, such data typically lack haplotype information (that is, the cis -connectivity of variants along individual chromosomes). This Review describes diverse recent experimental methods by which genetic variants can be resolved into haplotypes, accompanying computational methods and important applications of these methods in genomics and biomedical science. Human genomes are diploid and, for their complete description and interpretation, it is necessary not only to discover the variation they contain but also to arrange it onto chromosomal haplotypes. Although whole-genome sequencing is becoming increasingly routine, nearly all such individual genomes are mostly unresolved with respect to haplotype, particularly for rare alleles, which remain poorly resolved by inferential methods. Here, we review emerging technologies for experimentally resolving (that is, 'phasing') haplotypes across individual whole-genome sequences. We also discuss computational methods relevant to their implementation, metrics for assessing their accuracy and completeness, and the relevance of haplotype information to applications of genome sequencing in research and clinical medicine.

In the 1970s, the introduced silver carp Hypophthalmichthys molitrix (which is indigenous to eastern Asia) escaped from southern U.S. aquaculture to spread throughout the Mississippi River basin, and since has steadily moved northward. This large, prolific filter-feeder reduces food availability for other fishes. It now has reached the threshold of the Laurentian Great Lakes, where it likely will significantly impact food chains and fisheries. Our study evaluates population genetic variability and differentiation of the silver carp using 10 nuclear DNA microsatellite loci, and sequences of two mitochondrial genes-cytochrome b and cytochrome c oxidase subunit 1, along with the nuclear ribosomal protein S7 gene intron 1. We analyze population samples from: two primary Great Lakes' invasion fronts (at the Illinois River outside of Chicago, IL in Lake Michigan and in the Wabash River, which leads into the Maumee River and western Lake Erie), the original establishment \"core\" in the Lower Mississippi River, and expansion areas in the Upper Mississippi and Missouri rivers. We analyze and compare our results with bighead and other invasive carps, and cyprinid relatives. Results reveal that the silver carp invasion possesses moderate levels of genetic diversity, with more mtDNA haplotypes and unique microsatellite alleles in the \"core\" Lower Mississippi River population, which also diverges the most. The two invasion fronts also significantly genetically differ. About 3% of individuals (including all populations except the Illinois River) contain a unique and very divergent mtDNA haplotype, which likely stems from historic introgression in Asia with female largescale silver carp H. harmandi. The nuclear microsatellites and S7 sequences of the introgressed individuals do not differ from silver carp and are very distant from bighead carp. These sequence variation data are employed to design and evaluate a targeted high-throughput metabarcoding sequence assay that identifies and distinguishes among species of invasive carps (i.e., silver, bighead, grass, black, and common carps, along with goldfish), as well as native cyprinids, using cytochrome b. Our assay further differentiates among selected silver carp haplotypes (including between H. molitrix and H. harmandi), for use in population genetics and future analyses of spread pathways. We test and evaluate this assay on environmental (e)DNA water samples from 48 bait shops in the Great Lakes' region (along the Lake Erie, Lake St. Clair, and Wabash River watersheds), using positive and negative controls and custom bioinformatic processing. Test results discern silver carp eDNA in four of the shops-three in Lake Erie and one in the Wabash River watershed-and bighead carp from one of the same Lake Erie venues, suggesting that retailers (who often source from established southerly populations) comprise another introduction vector. Our overall findings thus provide key population genetic and phylogenetic data for understanding and tracing introductions, vectors, and spread pathways for silver carp, their variants, and their relatives.

Circulating cell-free DNA (cfDNA) has received increasing interest as an apparent breakthrough approach in diagnostics, personalized medicine, and tumor biology. However, the structural features of cfDNA are poorly characterized. Specifically, the literature has discrepancies with regards to cfDNA size profile. We performed a blinded study of the distribution of cfDNA fragment sizes in cancer patient plasma (n = 11), by various ultra-deep-sequencing approaches and quantitative PCR (Q-PCR). Whole-genome sequencing of single-stranded DNA library preparation (SSP-S) revealed that nearly half of the total cfDNA fragment number are below 120 nucleotides, which are not readily detectable by standard double-stranded DNA library preparation (DSP) protocols. Fractional size distribution of cancer patient circulating DNA was very similar using both SSP-S-based or Q-PCR-based methods also revealing that high molecular weight (over 350 bp) cfDNA is a minor component (~2%). These extra small detected cfDNA fragments may mostly result from nicks occurring in blood circulation in one or both DNA strands, which are subsequently revealed through the denaturation step of the SSP and Q-PCR procedures. Detailed analysis of the data suggested that most of the detectable cfDNA in blood has a nucleosome footprint (∼10-bp periodicity repeats). The nucleosome is thus the most stabilizing structure of DNA in the circulation. cfDNA molecules, which are initially packed in chromatin, are released from cells and are then dynamically degraded in blood both within and between nucleosomes or transcription factor-associated subcomplexes. While this study provides new insights into cfDNA size profiles harmonizing sequencing and Q-PCR findings, our data validate the use of a specific Q-PCR method and SSP-S for obtaining an optimal qualitative and quantitative analytical signal.

Painful diabetic peripheral neuropathy occurs in approximately 25% of patients with diabetes mellitus who are treated in the office setting and significantly affects quality of life. It typically causes burning pain, paresthesias, and numbness in a stocking-glove pattern that progresses proximally from the feet and hands. Clinicians should carefully consider the patient's goals and functional status and potential adverse effects of medication when choosing a treatment for painful diabetic peripheral neuropathy. Pregabalin and duloxetine are the only medications approved by the U.S. Food and Drug Administration for treating this disorder. Based on current practice guidelines, these medications, with gabapentin and amitriptyline, should be considered for the initial treatment. Second-line therapy includes opioid-like medications (tramadol and tapentadol), venlafaxine, desvenlafaxine, and topical agents (lidocaine patches and capsaicin cream). Isosorbide dinitrate spray and transcutaneous electrical nerve stimulation may provide relief in some patients and can be considered at any point during therapy. Opioids and selective serotonin reuptake inhibitors are optional third-line medications. Acupuncture, traditional Chinese medicine, alpha lipoic acid, acetyl-L-carnitine, primrose oil, and electromagnetic field application lack high-quality evidence to support their use.

False positive results for trisomy 18 from DNA-based noninvasive prenatal screening were caused, in two of the four patients who were evaluated, by maternal copy-number variation in chromosome 18. Methods of noninvasive prenatal screening 1 have advanced rapidly in clinical practice, with aneuploidy screening based on analysis of circulating cfDNA now routinely offered to women with high-risk pregnancies. Owing to the high reported accuracy of these screening tests, 2 , 3 attention has shifted to low-risk cohorts, in which the reduced incidence of aneuploidy may limit the positive predictive value of noninvasive prenatal screening. 4 A recent prospective analysis of cfDNA-based noninvasive prenatal screening in 1914 low-risk pregnancies showed false positive rates of 0.3%, 0.2%, and 0.1% for trisomies 21, 18, and 13, respectively — rates that were lower than those observed with . . .

Arthropods, including insects and arachnids, significantly affect humans as vectors for infectious diseases. Arthropod bites and stings commonly cause minor, usually self-limited reactions; however, some species are associated with more severe complications. Spider bites are rarely life-threatening. There are two medically relevant spiders in the United States. Widow spider (Latrodectus) envenomation can cause muscle spasm and severe pain that should be treated with analgesics and benzodiazepines. Antivenom is not widely available in the United States but may be considered for severe, refractory cases. Recluse spider (Loxosceles) bites are often overdiagnosed, should be treated supportively, and only rarely cause skin necrosis. Centruroides scorpions are the only medically relevant genus in the United States. Envenomation causes neuromuscular and autonomic dysfunction, which should be treated with analgesics, benzodiazepines, supportive care, and, in severe cases, antivenom. Hymenoptera, specifically bees, wasps, hornets, and fire ants, account for the most arthropod-related deaths in humans, most commonly by severe allergic reactions to envenomation. In severe cases, patients are treated with analgesia, local wound care, and systemic glucocorticoids. Diptera include flies and mosquitoes. The direct effects of their bites are usually minor and treated symptomatically; however, they are vectors for numerous infectious diseases. Arthropod bite and sting prevention strategies include avoiding high-risk areas, covering exposed skin, and wearing permethrin-impregnated clothing. N,N-diethyl- m-toluamide (DEET) 20% to 50% is the most studied and widely recommended insect repellant.

Drug resistance diagnostics that rely on the detection of resistance-related mutations could expedite patient care and TB eradication. We perform minimum inhibitory concentration testing for 12 anti-TB drugs together with Illumina whole-genome sequencing on 1452 clinical Mycobacterium tuberculosis (MTB) isolates. We evaluate genome-wide associations between mutations in MTB genes or non-coding regions and resistance, followed by validation in an independent data set of 792 patient isolates. We confirm associations at 13 non-canonical loci, with two involving non-coding regions. Promoter mutations are measured to have smaller average effects on resistance than gene body mutations. We estimate the heritability of the resistance phenotype to 11 anti-TB drugs and identify a lower than expected contribution from known resistance genes. This study highlights the complexity of the genomic mechanisms associated with the MTB resistance phenotype, including the relatively large number of potentially causal loci, and emphasizes the contribution of the non-coding portion of the genome. Resistance to antibiotics hampers the treatment of infectious diseases such as tuberculosis (TB). Here, Farhat et al. perform genome-wide association testing for minimum inhibitory concentration (MIC) of 12 anti-TB drugs in whole-genome sequenced clinical M. tuberculosis isolates and identify 13 genomic loci.

Background Given that maintaining the health of teachers and students is of the utmost importance, this study explored potential predictors of U.S. teachers’ decision to receive the COVID-19 vaccine, an evidence-based public health measure. The present study explored whether teachers’ demographics (i.e., gender, race, age, and grade taught), personal characteristics (i.e., awareness and nonjudgmental orientation as components of mindfulness, and anxiety), and state characteristics (i.e., gubernatorial party) were associated with their decision to receive the COVID-19 vaccine. Method Five hundred sixteen Kindergarten-12th grade teachers from across the U.S. participated in April 2022. Results Results from stepwise generalized linear mixed effects models indicated that teachers who were women (vs. men), White (vs. teachers of color), and younger (vs. older) were less likely to be vaccinated. Awareness skills were associated with greater odds of vaccination, whereas a nonjudgmental orientation and anxiety were associated with reduced odds of vaccination. Conclusions This study provides insight into demographic, personal, and state-level influences associated with teachers’ decision to receive the COVID-19 vaccine. Findings highlight the importance of targeted efforts to increase adherence to public health guidelines so that schools can reopen swiftly and safely in future public health crises.

We report a novel variant in ACAA2 that causes hepatitis and hypoglycemia during infancy and lipodystrophy during adulthood accompanied by elevated plasma long chain acylcarnitines.